Palladium catalyzed synthesis of aminoaldehyde intermediates

Abstract

Provided herein are processes for the synthesis of substituted fluoroalkyl azetidinyl-amino-benzaldehyde derivatives.

1 . A process (P1) for preparing a compound of formula (I) or a salt thereof,
 the process comprising the steps:   
       
         
           
           
               
               
           
         
         (1) reacting a reaction mixture comprising (a) an organic solvent comprising toluene, dioxane, or t-amyl alcohol; (b) a compound of formula (II); (c) a compound of formula (III) or a salt thereof; (d) a Pd catalyst; and (e) a base to form a compound of formula (1a) according to step 1 below: 
       
       
         
           
           
               
               
           
         
         wherein,
 Ring A is phenyl or pyridinyl; 
 X is halo, tosylate, mesylate, or triflate; 
 PG is a protected aldehyde, wherein X and PG are para to each other on Ring A; 
 R 1  is H, F, Cl, or CN; 
 each R 2  is independently halo, Me, or CN; 
 n is an integer of 1, 2, 3, 4, or 5; 
 p is an integer of 0, 1, or 2; 
 the base comprises an alkoxide base; and 
 Pd catalyst comprises the formula [Pd(L)(allyl)](X 1 ), wherein, 
 L is selected from 1,1′-Bis(diphenylphosphino)ferrocene (dppf) or a Xanthphos-derivative having formula (T); and 
 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           R a  and R b  are each independently hydrogen or C 1-3 alkyl; 
           R c , R d , R e , and R f  are each independently hydrogen, halogen, NH 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, or C 1-3 haloalkyl; and 
           q, r, s, and u are each independently an integer of 0-5; and 
           X 1  is halo, OMs, or OTf; and 
         
         (2) deprotecting the compound of formula (1a) in a reaction mixture comprising an aqueous acid to form the compound of formula (I) according to step 2 below: 
       
       
         
           
           
               
               
           
         
         wherein, the aqueous acid is HCl, HNO 3 , H 3 PO 4 , NaH 2 PO 4 , H 2 SO 4 , a sulfonic acid, or a carboxylic acid; 
       
     
     
         2 . The process of  claim 1 , wherein Ring A is phenyl. 
     
     
         3 . (canceled) 
     
     
         4 . The process of  claim 1 , wherein X is halo. 
     
     
         5 . The process of  claim 1 , wherein X is Br. 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The process of  claim 1 , wherein n is 3. 
     
     
         9 .- 10 . (canceled) 
     
     
         11 . The process of  claim 1 , wherein R 1  is F. 
     
     
         12 - 16 . (canceled) 
     
     
         17 . The process of  claim 1 , wherein each R 2  is independently F and p is 2. 
     
     
         18 . The process of  claim 1 , wherein PG is a diethyl acetal. 
     
     
         19 - 20 . (canceled) 
     
     
         21 . The process of  claim 1 , wherein the base is sodium tert-pentoxide, sodium tert-butoxide, potassium tert-pentoxide or potassium tert-butoxide. 
     
     
         22 . The process of  claim 1 , wherein the base is sodium tert-pentoxide or sodium tert-butoxide. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The process of  claim 1 , wherein L of the Pd catalyst comprises 1,1′-Bis(diphenylphosphino)ferrocene (dppf). 
     
     
         26 . The process of  claim 25 , wherein the Pd catalyst comprises formula [(dppf)Pd(allyl)]OTf. 
     
     
         27 . The process of  claim 1 , wherein L of the Pd catalyst comprises a Xanthphos-derivative having formula (T); 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  and R b  are the same and are each independently hydrogen or C 1-6 alkyl; 
 R c , R d , R e , and R f  are the same and are each independently hydrogen, halogen, N C 1-3 alkyl, C 1-3 alkoxy; and 
 q, r, s, and u are each independently an integer of 0.1, or 2. 
 
     
     
         28 - 29 . (canceled) 
     
     
         30 . The process of  claim 1 , wherein R c , R d , R e , and R f  are independently hydrogen or C 1-3 alkoxy. 
     
     
         31 . (canceled) 
     
     
         32 . The process of  claim 1 , wherein the L is a compound of formula (T) comprising a compound having a CAS No. selected from the group consisting of 161265-03-8, 205497-65-0, 2119686-40-5, 2119686-45-0, 2119686-39-2, 2119686-51-8, 2119686-52-9, 2119686-38-1, 1810068-85-9, 2119686-44-9, 2254460-12-1, 2119686-37-0, 2119686-49-4, 2119686-53-0, 2119686-36-9, 2119686-48-3, 2119686-43-8, 1182710-75-3, 2143143-32-0, 2119686-35-8, 2119686-42-7, 2119686-13-2, 2119686-12-1, 2300982-02-7, 2172792-28-6, 2231776-00-2, 2119686-41-6, 221462-97-1, 2300978-33-8, 1372784-49-0, 757964-78-6, 2119686-47-2, 805248-24-2, 796113-87-6, 2119686-50-7, 2143143-50-2, 2143143-49-9, 2119686-46-1, 1607019-61-3, 2143143-36-4, 2143143-48-8, 757964-80-0, 805248-23-1, 2143143-37-5, 2904636-03-7, 2143143-38-6, 2143143-34-2, 2143143-47-7, 1642150-80-8, 639477-10-4, 2143143-42-2, 2143143-52-4, 2143143-44-4, 2143143-39-7, 885029-01-6, 885028-98-8, 2143143-35-3, 2143143-51-3, 1215039-22-7, 2143143-53-5, 454479-88-0, 1446696-38-3, 2143143-33-1, 2143143-45-5, 791136-90-8, 454479-87-9, 1329705-38-5, 221463-01-0, 791136-91-9, 251941-32-9, 190788-99-9, 2143143-43-3, 2143143-40-0, 1329705-34-1, 889676-72-6, 462945-71-7, 251941-33-0, 450417-22-8, 450417-21-7, 2143143-46-6, 2143143-41-1, 885029-00-5, 1372784-48-9, 757964-79-7, 454479-85-7, 791136-92-0, 2136630-99-2, 885029-02-7, 1559060-17-1, 1372784-47-8, 805248-26-4, 796113-88-7, 2760688-12-6, 343256-85-9, 805248-25-3, 705282-10-6, 1330003-46-7, 1329705-36-3, 462945-76-2, 2459616-84-1, 2411643-30-4, 796113-86-5, 449214-10-2, 215792-51-1, 262420-61-1, or 594815-59-5. 
     
     
         33 . (canceled) 
     
     
         34 . The process of claim  0 , wherein L is a compound of formula (T) comprising a compound having formula: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The process of claim  0 , wherein L is a compound of formula (T) comprising a compound having formula: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The process of  claim 1 , wherein the Pd catalyst comprises a compound of formula [(Xanthphos)Pd(allyl)]CI having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         37 - 38 . (canceled) 
     
     
         39 . The process of  claim 1 , wherein the Pd-ligand catalyst is present at about 0.1%, 0.125%, 0.25%, or about 0.5 mol %. 
     
     
         40 . (canceled) 
     
     
         41 . The process of  claim 1 , wherein the aqueous acid is acetic acid, formic acid, or oxalic acid. 
     
     
         42 . The process of  claim 1 , wherein the aqueous acid is acetic acid. 
     
     
         43 - 46 . (canceled) 
     
     
         47 . The process of  claim 1 , wherein step 1 is performed at a temperature of 60° C. +/−10° C. 
     
     
         48 . The process of  claim 1 , wherein Step 2 further comprises crystalization of the compound of formula (I) following the deprotection of the compound of formula (1a) by adding reaction mixture comprising the compound of formula (I) onto an aqueous solution comprising a base. 
     
     
         49 . (canceled) 
     
     
         50 . The process of  claim 1 , wherein
 (i) the compound of formula (II) comprises a compound of formula:   
       
         
           
           
               
               
           
         
       
       and
 (ii) the compound of formula (III) comprises a compound of formula: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof.. 
     
     
         51 - 52 . (canceled) 
     
     
         53 . The process of  claim 1 , wherein the compound of formula (III) is not a salt. 
     
     
         54 . The process of  claim 1 , wherein the compound of formula (I) comprises a compound of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         55 - 56 . (canceled) 
     
     
         57 . A process for synthesis of a compound of formula (1): 
       
         
           
           
               
               
           
         
       
       wherein the process comprises the steps of:
 A) reacting a compound of formula (2) 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula (3) 
       
         
           
           
               
               
           
         
       
       in a reaction mixture comprising toluene, a Pd-ligand catalyst comprising [(Xanthphos)Pd(allyl)]CI, and a base selected from sodium tert-pentoxide or sodium tert-butoxide, thereby synthesizing a compound of formula (1a) 
       
         
           
           
               
               
           
         
       
       and
 (B) deprotecting the compound of formula (1a) of step 1 in a reaction mixture comprising toluene and an aqueous acid, thereby synthesizing the compound of formula 1. 
 
     
     
         58 . The process of claim  0 , wherein the base is sodium tert-pentoxide. 
     
     
         59 - 62 . (canceled) 
     
     
         63 . The process of  claim 57 , wherein step A is performed at a temperature of 60° C. +/−10° C. 
     
     
         64 . The process of  claim 57 , wherein Step 2 further comprises crystalization of the compound of formula (1) following the deprotection of the compound of formula (1a) by adding reaction mixture comprising the compound of formula (1) onto an aqueous solution comprising a base. 
     
     
         65 . (canceled)